DSF is dedicated to funding the highest caliber research on Dravet syndrome and associated epilepsies. Our focus is on research projects that will find new treatments and improve the quality of life for those living with an ion channel epilepsy. DSF places a high priority on funding research that has a clear path to genetic understanding, clinical application, and/or therapeutic development. Researchers interested in applying for a DSF Research Grant Award can learn more here

 

To date, DSF has allocated over $2 million to the following research projects:

 

2014 Awards

Theodore R. Cummins, PhD
DSF Research Award – $150,000 (2 year project)
Targeting resurgent sodium currents for treatment of Dravet syndrome
Dravet syndrome (DS) can be devastating and new treatment strategies are needed. In many individuals with DS, genetic abnormalities reduce the activity of the Nav1.1 sodium channel. This reduces inhibitory tone, leading to overactive brain networks and seizures. Reducing the activity of Nav1.6 sodium channels could restore the balance between excitation and inhibition, effectively normalizing network activity. This project will study Nav1.1 and Nav 1.6 channels identified in patients with different types of epilepsy. The action of several promising compounds, including cannabidiol, on these human brain sodium channels and on brain slices from a mouse DS model will be examined. These experiments should help develop a novel treatment strategy and potential drug candidates for Dravet syndrome.
 
Alfred L. George, Jr., MD
DSF Research Award – $150,000 (2 year project)
Novel Pharmacological Therapy for Dravet Syndrome 
Dr. George and his collaborators Dr. Jennifer Kearney and Dr. Christopher Thompson will investigate the mechanisms underlying a serendipitous observation that GS967, a novel compound with unique effects on sodium channels, prevents premature death in a mouse model of Dravet syndrome. Specifically, they will determine if GS967 prevents seizures and, if it does, then they will examine how it affects electrical activity in the brain. Because GS967 has many properties associated with a successful drug, the investigators hope that their studies will guide further development of this and related chemical compounds as potential treatments for Dravet syndrome and other childhood epilepsies for which there are no cures.
 
MacKenzie Howard, PhD
DSF Postdoctoral Fellowship – $50,000 (1 year project)
Neural progenitor cell transplantation for the study and treatment of Dravet syndrome 
Dr. Howard’s first research goal is to test the effectiveness of cell transplantation therapy for treating Dravet syndrome in a mouse model. This technique involves transplanting non-DS cells into a brain region called the hippocampus, where they develop into specialized inhibitory neurons. Such transplantation has been shown to reduce both seizures and comorbidities in other mouse models of epilepsy. His second goal is to use this technique to transplant DS neurons into the hippocampus of non-DS mice. This will allow him to study how the DS neurons develop, connect, and communicate with other cells in a seizure-free environment and give insight into how various functions of individual neurons are altered.
 
Jacy Wagnon, PhD
DSF Postdoctoral Fellowship – $50,000 (1 year project)
Brain transcriptomes in SCN1A and SCN8A related epileptic encephalopathies
The majority of Dravet syndrome cases are caused by mutations in the sodium channel gene SCN1A. Mutations in the related gene SCN8A have recently been discovered in patients with related disorders. Mutations in SCN1A and SCN8A cause severe, early-onset, drug-resistant seizures with a high risk for SUDEP (sudden unexpected death in epilepsy). Mouse models carrying patient mutations in SCN1A and SCN8A exhibit seizures and premature death. Dr. Wagnon will analyze gene expression in these two mouse models to identify common, shared pathological pathways that will provide new targets for treatment and prevention of seizures and SUDEP.

 

2013 Awards

Michael Hammer, PhD
DSF Research Award – $184,000 (2 year project)
Identifying modifier genes in patients with SCN1a haploinsufficiency using whole exome sequencing
Two questions commonly asked by parents after their child has been diagnosed with Dravet syndrome (DS) are (1) Is this genetic and am I responsible?, and (2) What does my child’s mutation type mean for future outcome? This project will attempt to help us better answer the second question. Most cases of DS are caused by mutations in the SCN1A gene. These mutations negatively affect how sodium ion channels work and result in epilepsies of varying severity. However, more than half of the cases of classical DS result from a single class of mutation (called a truncation) that causes one of the two copies of the gene that we usually inherit from our parents to be lost. This research project will explore the role that other genes, sometimes known as “modifiers”, may play in causing clinical variation among patients with truncation mutations at SCN1A.
 
Se Hee Kim, MD and Linda Laux, MD
DSF Research Award – $50,000 (1 year project)
Predictive Factors for Long-Term Cognitive Outcome in Dravet Syndrome
Correct diagnosis and subsequent adjustments of antiepileptic drugs improve seizure control and cognitive performance in patients with Dravet syndrome. However, association between early diagnosis or early appropriate medical therapy and improved long term development remains presumptive. Dr. Laux and Dr. Kim propose to identify predictive factors for favorable cognitive outcome, in cohort of 135 Dravet syndrome patients followed from 2008 to 2013 at the Ann & Robert H. Lurie Children’s Hospital Northwestern University. They believe that early detection and early appropriate management will lead to a better long-term cognitive outcome in Dravet syndrome patients.
 
Yvonne Wu, MD, MPH
DSF Research Award – $163,000 (18 month project)
Incidence and Predictors of DS: A Population Based Study
The frequency of Dravet syndrome in the general population is unknown. Making an early diagnosis is crucial to providing optimal treatment and improving long-term outcome. Although early predictors of Dravet syndrome have been described, these have yet to be validated in a general U.S. population. We hypothesize that Dravet syndrome is more common than previously recognized, and that reliable predictors during the first year of life indicate which infants with seizures will likely go on to develop Dravet syndrome. In a large birth cohort of over 120,000 infants born in Kaiser Permanente Medical Care Program in Northern California, we will review all inpatient and outpatient medical records to determine the incidence of Dravet syndrome based on established clinical criteria, and determine how many of these individuals have undergone genetic testing. We will then determine the seizure characteristics that increase the risk of Dravet syndrome. Our overall goal is to raise awareness of this often devastating disorder by determining the incidence of Dravet syndrome in the general population, and to find new ways to improve early diagnosis, and thus improve quality of care.
 
Jokūbas Žiburkus, PhD
DSF Research Grant – $184,000 (2 year project)
Adenosine A1 Agonist Control of Seizure Activity in Dravet Syndrome

Jokūbas Žiburkus’ laboratory at the University of Houston found that a neurotransmitter-like molecure – adenosine A1 receptor agonist, can effectively control fever-induced or febrile seizures, in a genetically engineered mouse model of Dravet syndrome. Žiburkus will test the hypothesis that the adenosine treatment during early development can prevent the later formation of chronic epilepsy and stabilize brain activity long-term. These studies will be accomplished in collaboration with Dr. Jeffrey Noebels from Baylor College of Medicine, using advanced electrophysiological and fast functional imaging techniques. In summary, Žiburkus stated: We are highly honored and excited by DSF’s sponsorship of this timely and important project. At this pre-clinical experimental stage we must be cautious about interpreting our results, yet hopeful about a potential that pharmacological modulation of the adenosine A1 receptor represents a novel and clincally relevant therapeutic target for Dravet syndrome and other forms of pediatric epilepsies.

 

Annapurna Poduri, MD, MPH

DSF Research Award – $110,000 (Year Two funding)

Genetics of Severe Early Onset Epilepsies

Epilepsy affects approximately one percent of the population and one in 200 children. A subset of children with epilepsy present in the first year of life with an early onset epileptic encephalopathy syndrome consisting of severe, medically intractable epilepsy and ultimately intellectual disability. While it is well established that genetic factors contribute substantially to the causes of epilepsy, there are still few known genetic etiologies for many of the early onset epileptic encephalopathies. These syndromes include severe myoclonic epilepsy of infancy (Dravet syndrome), infantile spasms, early infantile epileptic encephalopathy with suppression bursts (Ohtahara syndrome), malignant migrating partial epilepsy of infancy, and early myoclonic epileptic encephalopathy. Though they are distinct clinical syndromes, the few genes identified to date with any of them have been associated with a range of phenotypes, such that the discovery of a new gene for any one syndrome would represent an important addition to the currently very limited list of potential genetic etiologies for this group of serious epilepsy conditions. These discoveries will deepen our understanding of the developmental pathways important in epilepsy and will point us toward novel approaches to rational pharmacological treatment for epilepsy.

 

2012 Awards

Jingqiong “Katty” Kang, MD, PhD

DSF/CURE Research Award – $150,000 (1 year project)

Probing synaptic changes in a novel mouse model of severe epilepsy with nanoparticle-enabled 3D super-resolution imaging
Dr. Kang’s work focuses on understanding the role of GABAA receptors (GABR) in the etiology of epilepsies, including Dravet Syndrome. Normal brain function requires precise balance between excitation and inhibition. Too much excitation or too little inhibition will result in seizures or epilepsy. GABR are a family of genes encoding a total of 19 protein subunits which, in different combinations, mediate the majority of brain inhibition. A single coding change, like point mutation, in the any of the genes of this protein family can cause different kinds of epilepsy. Some of these epilepsies are mild and remit as children grow up but some are severe and may present with many other neurodevelopmental defects for unknown reasons. Dr. Kang’s team will try to understand the mechanisms underlying the pathophysiology of epilepsy as caused by mutations in GABR, as well the phenotypic variations, and to develop mechanism-based therapeutic strategies. View paper published in Annals of Neurology here

 

Annapurna Poduri, MD, MPH

DSF Research Award – $110,000 (1 year project)

Genetics of Severe Early Onset Epilepsies

Epilepsy affects approximately one percent of the population and one in 200 children. A subset of children with epilepsy present in the first year of life with an early onset epileptic encephalopathy syndrome consisting of severe, medically intractable epilepsy and ultimately intellectual disability. While it is well established that genetic factors contribute substantially to the causes of epilepsy, there are still few known genetic etiologies for many of the early onset epileptic encephalopathies. These syndromes include severe myoclonic epilepsy of infancy (Dravet syndrome), infantile spasms, early infantile epileptic encephalopathy with suppression bursts (Ohtahara syndrome), malignant migrating partial epilepsy of infancy, and early myoclonic epileptic encephalopathy. Though they are distinct clinical syndromes, the few genes identified to date with any of them have been associated with a range of phenotypes, such that the discovery of a new gene for any one syndrome would represent an important addition to the currently very limited list of potential genetic etiologies for this group of serious epilepsy conditions. These discoveries will deepen our understanding of the developmental pathways important in epilepsy and will point us toward novel approaches to rational pharmacological treatment for epilepsy.

 

2011 Awards

Jack M. Parent, MD

DSF Research Award – $250,000 (2 year project)

Readthrough Treatment of Dravet Syndrome Caused by Nonsense SCN1A Mutations
Dr. Parent and collaborators Dr. Lori Isom and Dr. Miriam Meisler will investigate whether readthrough therapy is a clinically viable treatment for Dravet syndrome patients who carry stop codon nonsense mutations. With a new technique, the induced pluripotent stem cell (iPSC) method, they have a unique opportunity to study the effects of mutations in neural cells by deriving neurons from patients’ own skin cells. In addition, they will collaborate with Dr. Richard Gatti, a Professor of Human Genetics at UCLA, who is developing new and improved readthrough compounds. Parent and his colleagues will test whether gentamicin, PTC124, or newer compounds will increase normal sodium channel levels and restore channel function in patient-derived neurons. They will also examine whether mice with a Dravet syndrome knock-in premature termination (stop) codon nonsense mutation (a point mutation in a sequence of DNA) will respond to readthrough therapy with a decrease in seizures and normalization of sodium channel function.

 

Scott Baraban, PhD

DSF Research Award – $100,000 (1 year project)

Drug Discovery in a Zebrafish Model of Dravet Syndrome

Dr. Baraban and his team are using Dravet syndrome zebrafish mutants to screen and identify novel pharmacological treatments for Dravet syndrome patients. Zebrafish are commonly used in research due to their genetic and experimental accessibility. This project was the starting point for Dr. Baraban’s newest research project (see below) recently co-funded by the DSF and CURE. View paper published in Nature Communications here

 

Scott Baraban, PhD

CURE & DSF Research Award – $250,000 (2 year project)

Gene Profiling and High-Throughput Drug Screening in a Zebrafish Model of Dravet Syndrome

Pediatric epilepsies are associated with developmental or cognitive co-morbidities and are not well controlled by available drugs. Unfortunately, existing drug discovery programs are not designed to address this problem, as they are primarily based on acute or acquired seizures in adult rodent models of the epilepsies. Dr. Baraban seeks to shift current research in the epilepsy field in two ways. First, by utilizing immature zebrafish models designed to mimic known single-gene mutations seen in children (for example, Dravet syndrome), he will establish a drug discovery program targeted at pediatric epilepsy that also incorporates large-scale microarray gene analysis. Second, by focusing on the zebrafish model, he will establish a new template for high-throughput cost-effective drug screening with distinct advantages over current rodent-based approaches. View update here

 

Opko Health, Inc.

DSF Research Award – $50,000 (1st year of project grant)

OPKO Research Project

More than 75% of children who have been diagnosed with Dravet syndrome have a defective SCN1A gene. As a result, the defective gene is not producing enough functional protein, leading to a diseased state. OPKO Health, Inc., a South Florida based pharmaceutical company, has developed new technology to increase SCN1A protein production. Early tests have shown a promising increase in this protein level in a Dravet patient’s fibroblast and in human cell lines, such as a neuroblastoma. This research is applicable to all mutation types. OPKO is committed to further the development of this work and to seek health authorities’ approvals worldwide. This project is overseen by Dr. Jane Hsiao, a grandparent of a child with Dravet syndrome.

 

2010 Awards

Sooky Koh, MD, PhD

DSF Research Award – $100,000 (1 year project)
Novel Therapies to Block Epileptogenesis in Dravet Syndrome Mice

Using a mouse model of Dravet syndrome, Dr. Koh and her colleagues will investigate three novel strategies to treat Dravet syndrome and understand epileptogenesis, the process by which the developing brain evolves to produce repeated seizures. They will utilize anti-inflammatory therapy; use dietary interventions; and, finally, investigate the use of an enriched environment on the impact and outcome of seizures. The promise of this research program is in identifying treatments that minimize the detrimental effects of recurrent seizures, modify disease progression, and prevent chronic epilepsy.

 

Sebastian Maier, MD, PhD and Massimo Mantegazza, PhD

CURE & DSF Research Award – $150,000 (1 year project)

Cardiac arrhythmias and SUDEP in SMEI and other Nav1.1 (SCN1A) related epilepsies

Dravet syndrome is a severe and drug resistant form of epilepsy, characterized by high mortality rates. Sudden unexpected death in epilepsy (SUDEP) is the most frequent cause of death for individuals with Dravet syndrome. The majority of individuals with Dravet syndrome carry mutations in a sodium channel subtype that is found in the brain, heart and nerves. Drs. Maier and Mantegazza will study the role of this sodium channel subtype in the heart of a mouse model of Dravet syndrome in order to investigate the occurrence and mechanism of arrhythmias and their possible involvement in SUDEP. View final report here

 

Jack M. Parent, MD & Ian Miller, MD

ICE & DSF Research Award (co-funded for life of project)

International Dravet Syndrome/Ion Channel Patient Registry (IICEPR)

This patient registry, owned by the University of Michigan and Miami Children’s Hospital, collects basic information and genetic test results of individuals with Dravet syndrome and related epilepsies worldwide and is available to all interested researchers at no cost. The establishment of this registry will expedite future clinical trials and will serve to improve communication of ideas amongst interested researchers, as well as assure rapid distribution of any new information that may benefit patients and their families.